Vascular disease, characterized as cardiovascular (CVD), cerebrovascular and peripheral vascular (PVD, also called peripheral arterial disease (PAD)), is the leading cause of death and disability in the Unites States, and is a rapidly emerging cause of death in the developing world. In the US alone, 2500 deaths per day are caused by CVD and the annual cost of the disease exceeds $400 billion (Rosmond, W., et al, Heart disease and stroke statistics-2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee, Circulation, Feb. 6, 2007; 115(5):e69-e171; Spinier S A, Pharmacotherapy, 2006; 26:209S-217S). Cerebrovascular disease includes Transient Ischemic attack (TIA) and stroke (brain attack). PVD or PAD is the presence of stenosis or occlusion in the aorta or arteries of the limbs, usually caused by atherosclerosis. PAD is prevalent after age 50 and is associated with significant increase in cardiovascular and cerebrovascular events (Sontheimer, D. L., Peripheral vascular disease: diagnosis and treatment, Am Fam Physician. Jun. 1, 2006; 73(11):1971-6). Approximately 240,000 TIAs, defined as a rapid disturbance of cerebral function due to cerebrovascular dysfunction lasting less than 24 hours, are diagnosed every year in the US and the numbers of undiagnosed TIAs are significantly higher (Johnson S. C., et al.; Ann Neurol. 2006, 60:301-313). The risk of a subsequent stroke after TIA is high, particularly in the first few days. So aggressive antiplatelet therapy is recommended to prevent further TIA or stroke.
Stroke, which includes ischemic (80% of strokes) and hemorrhagic, result from sudden onset of neurological deficit from interrupted blood supply to certain brain areas. Ischemic stroke results from embolic occlusion of large cerebral blood vessels or plaque buildup in the walls of blood vessels. High blood pressure and other factors can cause the plaque to rupture, triggering the platelets to aggregate and form a clot. Currently 700,000 Americans per year suffer a stroke and about 29% of these patients over 65 years of age die within 1 year. Worldwide, stroke is the third leading cause of death and severe disability in adults, with 20.5 million strokes and 5.5 million deaths (American Heart Association, Heart Disease and Stroke Statistics-2005 update).
Thrombosis, defined by local blood clotting, can occur in the arterial or the venous circulation. Platelet activation is a common factor in inflammatory diseases such as vascular disease (May A. E., et al., Atheroscier Thromb Vasc Biol. 2008; 28: s5-s10). Though enucleated, platelets can synthesize proteins by translational mechanisms, and a complex membranous system that allows them to store and rapidly release a variety of factors, such as monoamines, adhesion proteins, growth factors, chemokines, cytokines, and coagulation factors. Upon activation, platelets adhere to the endothelium and release adhesion factors, such as fibrogen.
Because thrombosis plays a major role in the pathogenesis of ischemic stroke, drugs that interfere with hemostasis and clot formation, such as anticoagulants and antiplatelet drugs are used for the management and prevention of stroke. Current treatment comprises thrombolytic therapy with tissue plasminogen activator (tPA), the only acute stroke treatment approved by the FDA in 1996 (Mitka, M., Rapid stroke treatment an elusive goal, JAMA, Apr. 9, 2008; 299(14):1653-4). Administration of tPA must be initiated within 3 hours of symptom onset, limiting practical use to a small proportion (less than 5%) of stroke victims, and is also associated with risk of intracerebral bleeding.
Current medical treatment for PVD includes administering anticoagulants to treat and prevent arterial or venous thrombosis, and reducing platelet aggregation by antiplatelet drugs such as aspirin and clopidogrel.
Because platelets have a role in the initiation and propagation of inflammation in their microenvironment, novel uses of antiplatelet drugs in the following conditions (infection, asthma and rhinitis, chronic obstructive pulmonary disease, cancer, rheumatoid arthritis, inflammatory bowel disease) are being investigated (Pitchford S. C.; Novel uses for anti-platelet agents as anti-inflammatory drugs, British J. Pharmacology, December 2007; 152(7): 987-1002).
Aspirin (Acetylsalicylic acid; ASA) irreversibly inhibits platelet cyclooxygenase 1, which catalyses the formation of thromboxane A2 (TXA2), a potent activator of platelets. Aspirin significantly reduces the risk of CVD (relative risk reduction of 25%) as well as reduces the risk of subsequent events (secondary prevention) in patients with previous history of CVD. But aspirin use is associated with risks such as stomach ulcers and bleeding. Moreover, the beneficial vascular effects are limited to lower doses, as high doses do not exhibit more effective vascular risk reduction and may blunt the antithrombic effect of low dose treatment (Patrono, C. & Rocca, B., Aspirin: Promise and resistance in the new millennium, Arterioscler. Throm. Vasc. Biol., 2008 March; 28(3):s25-32.). There have been several attempts to enhance the benefits of aspirin, using other antiplatelet drugs with different pharmacological actions on the platelet. However, use of drugs such as clopidogrel, prasugrel, ticlopidine, or dipyrimadole have so far not produced any significant improvements from treatment with aspirin alone, especially when one considers the high cost of these medications and the increased incidence of bleeding.
Dipyridamole (DP) is a phosphodiesterase inhibitor that increases the intracellular levels of cyclic AMP and cyclic GMP, and inhibits the uptake of adenosine, thereby reversibly inhibiting platelet aggregation and platelet-mediated thrombus formation.
Other anti-thrombotic drugs include ADP-receptor antagonists, αIIbβ-3-Intergrin inhibitors, and Protease-activated-receptor-1 (PAR1) inhibitors. ADP-receptor antagonists, like ticlopidine, clopidogrel and prasugrel, inhibit platelet activation by blocking ADP receptor P2Y12. Clopidogrel, in combination with aspirin is used for the prevention of acute coronary syndromes, secondary prevention of cardiovascular events, and stent thrombosis, whereas ticlopidine is not currently used due to serious side effects such as rash, neutropenia, and agranulocytosis. αIIbβ-3-intergrin inhibitors reduce platelet aggregation by blocking the binding of activated platelets to fibrinogen and other ligands. However, inhibitors like abiciximab, eptifibatide, and tirofiban are used only for short-term treatment of acute coronary syndromes as intravenous injections; oral formulations of these drugs are not used due to serious side effects.
Anticoagulant drugs reduce the activity of various proteases in the coagulation cascade. The major anticoagulant classes are vitamin K antagonists, heparins and inhibitors of factor Xa and thrombin. These drugs have serious side effects including bleeding. Antiplatelets drugs are used in acute thrombotic events and are also used prophylactically to reduce the incidence of arterial thrombosis in patients with CVD. The primary targets of antiplatelet therapy are molecules involved in platelet activation and aggregation. Another method for treatment for acute thrombotic events is the use of fibrinolytic agents (clot busters) like plasminogen activator and streptokinase. However this treatment has a short window of few hours to be successful. Recent studies have identified a number of novel platelet receptors and signaling mechanisms as targets for antiplatelet therapy.
The goal of secondary stroke prevention in patients who have suffered a stroke or transient ischemic attack (TIA) is to prevent recurrent cerebrovascular events. The rate of a recurrent stroke is estimated to be between 25-40% within 5 years, after the initial event. The strategy for secondary prevention includes risk factor modification, drug therapy, and surgery, when appropriate. The use of antiplatelet agents to treat or prevent recurrent TIA and stroke is a popular approach. There are numerous studies supporting the efficacy of aspirin, clopidogrel, and dipyridamole alone or in combination.
There is strong data to support the contention that long-term aspirin use reduces the risks of myocardial infarction, stroke, and vascular related deaths in patients with vascular disease. Up to 30% of patients on aspirin antithrombotic therapy have recurrent major vascular events each year, a phenomenon termed aspirin resistance. Patients who are resistant to aspirin are at a higher risk for cardiovascular morbidity long term than patients who respond to aspirin therapy (Krasopoulos, G. et al; Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis, Jan. 26, 2008, Br Med J; 336(7637):195-8). Variable antiplatelet responses to other antithrombotic drugs, like clopidogrel, have also been reported by several studies. The mechanisms responsible for this decreased platelet response have not been clearly determined. But clopidogrel resistance is a marker for increased risk of recurrent vascular events (Campo, G. et al; Poor responsiveness to clopidogrel: drug-specific or class-effect mechanism? Evidence from a clopidogrel-to-ticlopidine crossover study; J Am Coll Cardiol, Sep. 18, 2007; 50(12):1132-7). Response to aspirin or clopidogrel may be modified by factors such as noncompliance, inadequate dose, poor absorption or metabolism, concomitant medications, and polymorphisms. Combination therapy with other antiplatelet agents is a therapeutic option in patients with aspirin or clopidogrel resistance. Duel antiplatelet therapies were first investigated using thienopyridines, drugs that block adenosine 5′-diphosphate-dependent activation of platelets mediated by ADP-P2Y12 receptors. Duel therapy using aspirin and thienopyridines such as clopidogrel and ticlopidine has been actively investigated. However, drug safety profiles and antiplatelet efficacy question the use of aspirin-thienopyridine duel antiplatelet therapies (Bhatt D. L., et al.; Clopidogrel for High Atherothromobitic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Investigators, Clopidogrel and aspirin versus aspirin alone for the prevention of atherothromobotic events, N Engl J Med; 2006; 354, 1706-1717). New, third generation thienopyridines, such as prasugrel, ticagrelor, and cangrelor, are currently being investigated.
An ideal antiplatelet drug—one that will prevent thrombosis, without promoting bleeding—has yet to be found. A promising new approach is combination therapy, administering new agents with existing antiplatelet and anticoagulant drugs, which might prove more effective than using a single class of drug. Dual antiplatelet therapy with combinations of aspirin and clopidogrel or aspirin and dipyridamole has limited applications in thrombotic disorders. But these combinations do not necessarily improve clinical efficacy and are associated with a substantial increase in bleeding risk. These strategies are far from ideal, as most treatments have severe adverse side effects, including internal bleeding, and aspirin/clopidorel resistance.
Despite increased understanding of thrombogenesis and vascular function, therapeutic strategies to ameliorate the impact of vascular diseases are far from satisfactory. There is an urgent and unmet medical need to enhance the efficacy of currently available antiplatelet drugs in preventing and treating the overwhelming burden of the number one cause of death and disability worldwide, vascular disease.